Abstract 5119: Nano-immunotherapy targeting PD-L1, PLK1, and TLR9 for treatment of non-small cell lung cancer
Authors: Moataz Reda, Worapol Ngamcherdtrakul, Ruijie Wang, Noah Crumrine, Cole Baker, Alyssa Wallstrum, Jeremy Saito, Natalie White, Wassana Yantasee
Journal: Cancer Research (2023)

Abstract Given the complexity of cancer, it is becoming apparent that combination therapy - in which complementary biological pathways are simultaneously targeted - is required to achieve clinically meaningful responses. To that end, PDX Pharma, in collaboration with Oregon Health &amp; Science University, has developed a proprietary nanoparticle platform (Pdx-NP™) that can effectively co-deliver a plethora of therapeutic modalities while maintaining a small size in saline (100 nm), suitable for infusion and tumor accumulation. This enables the targeting of complementary cancer and immune pathways, leading to synergistic clinical benefits. Herein, we report on the second generation ARAC-02 (Antigen Release Agent and Checkpoint Inhibitor) which is designed to improve the efficacy of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). While ICIs have improved survival in a subset of patients with advanced NSCLC, only a minority of patients respond to ICIs, highlighting the need for combination immunotherapy. ARAC-02 co-delivers a polo-like kinase 1 (PLK1)-targeted therapy (volasertib), a PD-L1 antibody, and the immune-stimulant CpG. These three agents were carefully selected based on their roles in cancer and immune pathways. Volasertib 1) selectively kills cancer cells, 2) modulates the immune-suppressive tumor microenvironment, and 3) upregulates PD-L1 expression in cancer cells, providing opportunity for targeted delivery with PD-L1 antibody on the nanoparticles. CpG is a TLR9 agonist that enhances antigen presentation to generate tumor-specific T cells. PD-L1 antibodies serve as tumor targeting agent for nanoparticle delivery as well as an ICI (i.e., PD-L1 degradation upon internalization with the nanoparticles), releasing the brakes and allowing T cells to attack the cancer. We found that the optimized ARAC-02 is preferentially internalized in PD-L1 expressing NSCLC cells, demonstrating a 10-fold greater uptake to PD-L1(high) NSCLC cells than PD-L1(low) normal cells. ARAC-02 effectively kills NSCLC cells regardless of their mutational status, while sparing normal cells. In a metastatic lung tumor model, ARAC-02 treatments reduced the tumor burden by 30-fold vs. saline control and 8-fold vs. the first generation ARAC (not containing CpG), whose effect was mainly mediated by CD8+ T cells. ARAC-02 was found to be safe to mice as assessed by body weight, serum biomarkers, and histology. Importantly, intravenous infusions of the platform was also found to be safe in a preliminary toxicology study in non-human primates. Due to its unique ability to catalyze various steps of the adaptive immune response, ARAC-02 is anticipated to provide superior outcomes in NSCLC and a broad range of tumor types regardless of baseline PD-L1 expression. Citation Format: Moataz Reda, Worapol Ngamcherdtrakul, Ruijie Wang, Noah Crumrine, Cole Baker, Alyssa Wallstrum, Jeremy Saito, Natalie White, Wassana Yantasee. Nano-immunotherapy targeting PD-L1, PLK1, and TLR9 for treatment of non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5119.